New anticonvulsants derived from 4-allyl-2-methoxyphenol (Eugenol): comparison with common antiepileptics in mice.

Abstract

The anticonvulsant activity (ED50) of three synthetic eugenol derivatives - phenyleugenol (PE), benzyleugenol (BE), phenylethyleugenol (PEE) - was compared to that of common antiepileptics - diphenyl-hydantoin (DPH), phenobarbital (PB), diazepam (DZ) - and the naturally occurring methyleugenol (ME) in the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazol-induced minimal seizure (s.c. PTZ) test. Neurotoxicity (ND50) and lethality (LD50) were determined in order to evaluate the protective index (PI = ND50/ED50) and the therapeutic index (TI = LD50/ED50). BE, PE and PEE are shown to be effective anticonvulsants by the MES test in mice with PIs equal to or higher than that of PB and DZ. Furthermore, BE and PEE were significantly more potent in rats than in mice. Experiments on ;the duration of protection revealed an immediate onset, a steady decline within the following 4 h and reappearance of activity 6-8 h after injection of PE, BE, and PEE but not ME. In the s.c. PTZ test in mice, the eugenol derivatives were active in increasing the latency to the first minimal seizure but less active in its prevention. As to the TIs, PEE showed a smaller margin of safety by the two tests than BE and PE. The latter compounds have high LD50s and consequently high TIs.